The effect of beta-blocker

on cardiovascular system
 Kuis
• 1. Apa itu Beta Blocker
• 2. Apa saja jenis-jenisnya?
• 3. Bagaimana Mekanisme Kerjanya?
• 4. Apa indikasi penggunaannya?
 Action in practical works
 How many systems involve in cardiovascular (CV)
functions?
 Describe the patho-physio-pharmacology of CV
functions
 Describe the pharmacology of sympathetic nervous
system
 What do the receptors do?
 Activation of -adrenergic receptors on the CV system
– Heart, blood vessels, kidney
 How do -blockers work?
 Blockade of beta-adrenergic receptors on the CV system
– Heart, blood vessels, kidney
 What are -blockers used for?
 Different Pharmacological Profiles of -Blockers
– Hypertension, heart failure
 Drug interaction -blockers with other CV agents
1. How many systems involve
in cardiovascular (CV)
functions?
 Autonomic
nervous
system (ANS)
 Renin
angiotensin
aldosteron
system (RAA)
 2. Describe the
pathophysiopharmacology
of CV functions
 Patho-physio-pharmacology
of CV functions
CNS BR

α2 β1 Heart
Sympathetic BP
Nerve
BV Ca++
α1
Ag Retention
Kidney
Na & water
β1 Renin
A-I A-II Aldosteron
ACE
 The Renin-Angiotensin system in
the development of high blood pressure
Non-ACE pathways ACE pathways
Angiotensinogen Kininogen
Non-renin
enzymes Renin Kallikrein

Angiotensin I Bradykinin
CAGE
t-PA Chymase ACE
Cathepsin G Cathepsin G
Chymase
Angiotensin II Inactive
Cathepsin G
peptides

AT1 AT2 NO
PG
• vasoconstriction • Vasodilation (?)
vasodilation
• aldosterone release, Na • Bradykinin, NO and
and fluid retention cGMP release
• cell proliferation, • Antiproliferation,
hypertrophy apoptosis stimulation,
• Sympathetic activation tissue regeneration
CAGE= Chymotrypsin like
Adapted from Hollerberg NK. Am J Med Care,1998;A(suppl7)5384-5387
Angiotensin Generating Enzyme
 3. Describe the
pharmacology of
sympathetic nervous
system
 Sympathomimetic amines
 Sympathetic Neurotransmitters
 Sympathetic Receptors
Sympathomimetic amines
 Sympathetic Neurotransmitters
• Preganglionic neurons
– Cholinergic = ( release acetylcholine )
 Sympathetic Neurotransmitters

• Postganglionic neurons:
– Release norepinepherine at target organs
– i.e. Adrenergic
• Adrenal medulla:
– Release epinepherine & norepinepherine into blood
– i.e. Adrenergic
 Sympathetic Receptors

• Located only on sympathetic target organs

• Respond only to norepinepherine released by
postganglionic neurons (precise effects) or
• Epinepherine & norepinepherine released by
adrenal medulla into blood (general effects)
4. What do the receptors
do?
 Adrenergic Agents
Mechanism of Action
Direct-acting sympathomimetic:
 Binds directly to the receptor and causes a
physiologic response
Indirect-acting sympathomimetic:
 Causes the release of catecholamine from the
storage sites (vesicles) in the nerve endings
 The catecholamine then binds to the receptors
and causes a physiologic response
Mixed-acting sympathomimetic
4. What do the receptors do?
 Activation of  receptors leads to
smooth muscle contraction
 Activation of 2 receptors leads to
smooth muscle relaxation
 Activation of 1 receptors leads to
smooth muscle contraction
(especially in heart)
Sympathetic Receptor Types
Receptor Effects
Alpha 1 • In walls of blood vessels leading to places other than skeletal
muscles, brain & lungs. Not on heart (cardiac muscle)
• Excites (constricts) certain blood vessels & in spincters
directing blood to skeletal muscles
• Dilates pupils.

Alpha 2 • On membranes of platelets.

• Promotes blood clotting
Beta 1 • On heart (cardiac muscle) & kidneys
• Cardiac Muscle increases heart rate & strength
Beta 2 • On coronary arteries, bronchioles & on smooth muscle walls
of digestive & urinary systems
• Depresses (dilates) smooth muscle in bronchioles &
coronary arteries increasing blood flow to heart and air flow
to lungs.
 Adrenergic Receptor Responses
to Stimulation
Organ Location Receptor Response
Cardio- Blood vessels alpha1 Constriction
vascular beta2 Dilatation
Cardiac muscle beta1 Increased
contractility
AV Node beta1 Increased
SA Node beta1 Increased
Respiratory Bronchial beta2 Dilatation/
muscles Relaxation
 Adrenergic Receptor Responses
to Stimulation
Organ Location Receptor Response
Gastro- Liver beta2 Glycogenolysis
intestinal Muscle beta2 Decreased
Sphincters alpha1 Constriction
Genito- Bladder alpha1 Constriction
urinary sphincter
Penis alpha1 Ejaculation
Uterus alpha1 Contraction
beta2 Relaxation
 Adrenergic Receptor Agonists and
Antagonists
-AR non selective
• Agonists: I > E > NE
• Antagonists: Propranolol, Nadolol,
Timolol
1-AR
• Agonists: Dobutamine, Dopamine
• Antagonists: Atenolol, Esmolol,
Metoprolol
2-AR
• Agonists: Albuterol, Ritodrine,
Tertbutaline, Salmeterol,
• Antagonists: Butoxamine
-AR nonselective
• Agonists: E > NE > > Iso,
Clonidine, Oxymetazoline
• Antagonists: Dibenamine,
Phenoxybenzamine,
Phentolamine, Tolazoline
1-AR
• Agonists: Phenylephrine,
Methoxamine
• Antagonists: Doxazosin,
Prazosin, Terasin,
2-AR
• Agonists: a-methyldopamine
• Antagonists: Yohimbine
 5. Activation of beta-
adrenergic receptors on
the CV system
 Beta-Adrenergic Receptors
All are located on postsynaptic
effector cells
 Beta1-adrenergic receptors
– located primarily in the heart
 Beta2-adrenergic receptors
– located in smooth muscle of the bronchioles,
arterioles, and visceral organs
 -receptor types
 β-adrenergic receptors respond
particularly to epinephrine and to such
blocking agents as propranolol.
 There are three known types of beta
receptor, designated β1, β2 and β3.
 β1-Adrenergic receptors are located mainly in
the heart.
 β2-Adrenergic receptors are located mainly in
the lungs, gastrointestinal tract, liver, uterus,
vascular smooth muscle, and skeletal muscle.
 β3-receptors are located in fat cells.
Stimulation of beta1-adrenergic
receptors on the myocardium,
AV node, and SA node results in
CARDIAC STIMULATION
 Increased force of contraction
(positive inotropic effect)
 Increased heart rate
(positive chronotropic effect)
 Increased conduction through the AV node
(positive dromotropic effect)
6. How do -blockers
work?
 How do -blockers work?
Mechanism for How It Works
 Beta-blockers "block" the effects of
catecholamines on beta-adrenergic
receptors.
 Beta blockers (sometimes written as β-
blockers)
Drug and Receptor
Competitive inhibition
 Blocking Agents
• Interfere with stimulatory or depressing effects of
neurotransmitters by blocking the receptors on
target organs.
Blocker

Action potential

Normal neurotransmitter can’t bind with receptor

because blocker covers the binding site
 7. Blockade of beta-
adrenergic receptors on
the CV system
 Mechanism of action
Beta Blocker

↓ activation of
Beta Blocker β1 receptor in ↓ CO
heart

↓ Renin ↓ angiotensin II ↓PR ↓BP

↓ aldosteron

↓ Na and
water ↓ blood
retention volume
8. What are -blockers
used for?
 What are -blockers used for?
Current Uses
 Treatment
– Angina pectoris (chest pain associated with lack of oxygen
to the heart)
– Arrhythmias (irregular heart rhythms)
– Heart attack
– Heart failure
– Hypertension (high blood pressure)
 Prevention
– Protects the heart in people who have coronary artery
disease
– Reduces risk of stroke
– Protective prior to non-cardiac surgery in persons at high
risk of complications
OVERSTIMULATION 

NORMAL STIM 

BLOCKING 
9. Differences Between
b-Blockers
Are There Differences Between
b-Blockers?
 b blockers are a heterogeneous class
– more than 15 agents available
 All are competitive antagonists
 Propranolol is prototype
 Classification is based on
 Beta subtypes selectivity
 Partial agonist activity
 Lipid solubility
 Local anesthetic action
Beta Blockers
 Non-specific -blockers
(antagonize both 1 and 2 receptors)
OH OH OH
OH H H
H O H N
O N O N
N

O N O
H

Propranolol Carteolol O Levobunolol M etipranolol

(OptiPranolol, Glaucoma)

OH OH OH
H H H
O N O N N
O
OH
H
HO N MeSO2
N
H
N
HO H Sotalol
(alsoinhibitsinwardpotassiumchannels
Nadolol Oxprenolol Pindolol intheheart)
(Corgard, bloodpressure, chest pain)

OH
H
O N
O Timolol
N
N
(oral formisBlocadren)
(Opthalm icformTim optol or Timoptic)
N S

Selective (1 cardioselective) -blockers

O
H O
H O
H O
H
O
H H H H H
O O N O N O N
H N
O N
O

N
H O O
2
H
N

O
O Meto
p r
olo
l
B e
ta
x o
l
ol Es
molo
l (
Lopr
ess
or,Novar
ti
s)
A
c
eb
ut
olo
l A
t
eno
l
ol (
Bet
opt
ic,L
okr
en) (
Bre
vib
loc
) (a
ls
o To
p r
ol-
XL,
B
eta
lo
c (
Astr
aZenec
a)
 Non-selective -blockers which
also antagonize at the 1 receptor

M
eO
O
H
H
O N O
H
O H
N

N H
O
H
La
bet
alo
l
Carved
il
ol O N
H2
(
N o
rmo
dyn
e,Tra
nda
te
)
(
C or
eg,GSK )
(
D i
lat
rend,Euca
rdic
,R o
ch
e)
 Beta Blockers
 Pharmacology
– Lipophilicity
– Membrane stabilizing effect
 Selective vs non-selective agents
 Propranolol is most common and most
dangerous
 Beta Blockers
 Toxic Dose
– 2-3 times therapeutic dose
 Signs and Symptoms
– Bradyarrhythmia
– Hypotension
– Decreases LOC
– Respiratory depression
– Seizure
– Ventricular arrhythmia
10. Drug interaction -
blockers with other CV
agents
First-line antihypertensive drugs
Diuretics

β– blockers ACE inhibitors

α1–blockers Ca antagonists

Angiotensin II antagonists
Drug interaction -blockers
with other CV agents
-blockers CV agents Results
Propranolol Hydrochlorothiazide
Atenolol Captopril
Propranolol Verapamil
Atenolol Nifedipin
Propranolol Valsartan
Atenolol Prazosin
Propranolol Aspirin
Atenolol Heparin
Propranolol Dipyridamole
Atenolol Caffeine
Propranolol Phenylpropanolamin
The effect of beta-blockers
in hypertensive patients
 Blood Pressure Regulation

Cardiac output X Peripheral Resistence

LOCAL
CARDIAC Heart rate Ionic
BARORECEPTOR Auto reg
Contractility
NERVOUS
SYMPATHETIC
RENAL FLUID VOLUME
• Sodium
• Minerolcorticoid Constrictor Dilator
alpha beta
HUMORAL

VASOLIDATOR VASOCONSTRICTOR
Prostaglandins, KININ ANGIOTENSIN, Catechols
 Low concentrations of drug

1 >   2 > 1 > 1 and D1

reflex 1-slight inc 1-strong inc 1-slight inc

D1- vasodil
Renal and
2-vasodil 2-vasodil mesenteric
Inc. blood vessels
 The effect of beta-blockers
in patients with heart failure
 -blockers

The effect of
-blockers
in patients
with
heart failure
 Different Pharmacological Profiles
of Beta-Blockers Studied in
Heart Failure
β1- β2- α1- Ancillary
β1- blocker blockade blockade blockade properties
ISA
Propranolol +++ +++ 0 0 0
Metoprolol +++ 0 0 0 0
Bisoprolol +++ 0 0 0 0
Bucindolol +++ +++ +(0) +(0) 0
Carvedilol +++ +++ +++ 0 +++(*)

*Antioxidant and antiproliferative.

The effect of beta-blockers
in patients with angina
 Pathophysiology of Angina Pectoris

Oxygen Demand
Double product = (Heart Rate) (Systolic Blood Pressure)
anti-ischemic effects of
β-blocker
Beta Blockers: Therapeutic Uses
 Anti-angina:
– decreases demand for myocardial oxygen
 Cardioprotective:
– inhibits stimulation by circulating
catecholamines
 Class II antidysrhythmic
 Antihypertensive
 Treatment of migraine headaches
 Glaucoma (topical use)
 Beta Blockers
 Prescribed for  Therapeutic effect
– Hypertension – 1 Cardiac influence
– Angina – 2 Peripheral

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